Elemental analysis in clinical practice Nicholas J Miller FRCPath, Laboratory Director, Biolab Medical Unit, ThermoFisher summer symposium 7 th June 2011, QEII Conference Centre
Nutritional Elements Macro minerals (7) Na, K, Cl (electrolytes) Ca, Mg, P (mainly bone) S (mainly amino acids) Trace elements = < 0.01% of the total body mass (9) Fe, Zn, Cu, Mn, I, Se, Mo, Co, Cr, Ultra-trace elements (7) As, B, F, Ni, Si, Sn,V
Trace elements are enzyme co-factors 1/3 of known enzymes require metals for their function Metalloenzymes Fe 2+, Fe 3+, Cu 2+, Zn 2+, Mn 2+, Co 2+ Metal-activated enzymes Na +, K +, Mg 2+, Ca 2+
Toxicity of metals Substitution for essential metals in enzymes, Interference with intracellular signaling pathways and with Ca 2+ metabolism, Induction of oxidative stress, Interference with DNA transcription, translation and repair.
Organism s performance Essential metals in human metabolism Optimum Window of essentiality Concentration of metal
Nutritional element profile in plasma Calcium, chromium, copper, iron, magnesium, manganese, selenium, sodium, zinc, Aluminium, cobalt, molybdenum and nickel, Usually red cell magnesium as well.
Magnesium Pumped into mammalian cells - but no big gradient, So dissimilar function from Na +, K +, Ca 2+, Plasma levels are maintained at the expense of intracellular stores, Mg-dependent enzymes in cytoplasm e.g. ATPases, + control of many reactions such as ATP pumps and cellular contraction.
Zinc The most common catalytic metal ion in the cytoplasm, with Zn-dependent enzymes involved in a great variety of reactions, Zn is required for regulation of DNA in eukaryotes, Zn deficiency has multiple effects, C. 20% of the world population is estimated to be Zn-deficient (Brown KH and Wuehler SE, 2000).
Copper Most of the plasma Cu is on the ferro-oxidase enzyme caeruloplasmin and increases in concentration in the acute phase reaction, Plasma Cu is low in Wilson s disease copper storage causing toxicity), (excess Otherwise plasma Cu is low in severe deficiency, as is erythrocyte SOD activity.
Selenium There are around 30 selenoproteins that may be found in the plasma, These include GSHPx & selenoprotein P, Erythrocyte Se reflects rbc GSHPx at the time of erythropoiesis, In practice plasma Se is the best index of Se deficiency (and ICPMS has revolutionised this analysis).
Chromium and Manganese ICPMS has greatly improved the measurement of these metals, which are found in plasma close to the analytical detection limit, Chromium levels fall progressively with age, Manganese is being added to the food chain, Analyse whole blood for assessment of toxic levels of Cr and Mn.
Molybdenum Humans consume 100 to 500 µg Mo/day rincipally from organ meats, whole-grain cereals, and legumes, Essential in humans, due to its role in three enzymes: Sulphite oxidase Xanthine oxidase Aldehyde oxidase The occurrence of Mb deficiency is unknown since this measurement has only recently become available.
Toxic elements in blood Cadmium, Lead, Mercury.
Two major mechanisms of heavy metal toxicity Binding to SH and nitro-groups of biomolecules, Cofactor substitution, conformational changes, etc. Oxidative damage due to direct catalysis of ROS production and/or to inhibition of ETC in mitochondria.
Uptake of toxic metals There are multiple pathways of metal uptake into the cell, Toxic metals use routes which have evolved for the uptake of essential metals, esp. via ion channels and carrier proteins, with limited transport across membranes, Greater uptake of toxic metals when supply of nutrient metals is limited.
Cadmium Cd is chemically similar to Zn and a contaminant of Zn products (e.g. galvanised steel, Actively taken up by plants (along with Zn), Much Cd in humans is from ingestion of food plants grown in a Cd-rich soil; also from smoke, diesel fumes etc., Toxicity via binding to SH groups and enzyme inhibition (IARC group 1 - known carcinogen), Chronic toxicity - kidney is major target organ, also lung damage and osteomalacia (Itai itai disease = ouch ouch), Chelation not recommended (potential for renal damage).
Lead Binds to SH groups and inhibits enzymes (esp. ALA-D, ferrochelatase), Divalent lead competes with calcium in signal transduction and nerve transmission, Affects cell membranes, ion transport, reproduction, Burtons lines - grey-blue lines of lead sulphide in gums, Chelation with EDTA or DMSA (use of penicillamine declining).
Childhood lead poisoning Symptoms of lead poisoning in children Neurological problems Learning disabilities Lowered intelligence Behavioral problems In severe cases - seizures, comas, and death
Childhood lead poisoning
Mercury There is a lack of agreement as to the significance of blood mercury levels, Mercurialentis - brown band around the eye from Hg deposition seen after chronic industrial exposure, Main UK sources of mercury appear to be dental amalgam and ingestion of certain fish, We find significant levels of mercury in the blood and hair of some subjects, with an increased mercury excretion in the urine after chelation challenge.
Elemental analysis for clinical use: Analysis of plasma collected into trace elementfree tubes for deficiencies of nutritional metals, Red cell analysis for Mg, Whole blood analysis for toxic levels, Chelation challenge and urine analysis for toxic metals.